White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after traumatic brain injury (TBI). A persistent pro-inflammatory microenvironment after TBI is considered one underlying mechanism that hinders oligodendrocyte precursor cell (OPCs) differentiation and maturation into myelinating oligodendrocytes (OLs). Accumulating evidence suggests that the different functional phenotypes of microglia/macrophages contribute considerably to the regulation of inflammatory status of injured WM and ultimately impact the WM integrity. Specifically, alternatively activated M2 microglia are essential for remyelination and WM repair because they resolve local inflammation, clear broken myelin sheath or cellular debris, and provide trophic factors that promote OPC differentiation. Interleukin-4 (IL-4) is thus far the best characterized inducer for M2 polarization of microglia/macrophages; however, its role in microglia regulation in WM and long term outcomes after TBI is not known. Our preliminary results show that post-treatment with IL-4 nanoparticle through intranasal delivery increased IL-4 levels in the brain and improved long-term neurological functions after controlled cortical impact (CCI). Remarkably, IL-4 treatment enhanced post-CCI WM functional integrity, as shown by increased amplitude of action potential conduction in myelinated fibers. We have found in vitro that in addition to promoting M2 polarization, IL-4 directly induces the differentiation of primary OPCs into mature OLs at nanomolar concentrations and that this effect of IL-4 on OPCs is mediated through the activation of PPAR?. In this proposal, we will focus on the novel action of IL-4 on WM integrity and explore the underlying mechanisms. We will test the overarching hypothesis that IL-4 promotes WM integrity and long-term neurological recovery after TBI by dual mechanisms, in that it 1) promotes OPC differentiation/ maturation via PPAR? activation and 2) potentiates microglia/macrophage polarization toward the beneficial M2 phenotype, which is essential for remyelination and WM repair in demyelinating brains. The Specific Aims to be tested are: Aim 1: Test the hypothesis that IL-4 post-treatment enhances WM integrity and long-term neurological recovery after TBI. IL-4 will be delivered into the brain by repeated intranasal administrations after CCI. The endpoints for assessment include neurological outcomes and various markers for WM integrity. Aim 2: Test the hypothesis that IL-4 induces OPC differentiation into mature OLs and promotes axonal remyelination via PPAR? activation. Aim 3: Test the hypothesis that IL-4 potentiates microglia/macrophage polarization into the inflammation-resolving, tissue repair-enhancing M2 phenotype and restores a healthy microenvironment for efficient WM repair. The success of this study will identify a novel immunotherapy to enhance rehabilitation and therefore improve quality of life for veterans suffering TBI.